In Europe and many developed countries, the preterm birth rate is generally 5-6%, and in the USA it has even risen to 12-13% in the last decades. By gestational age, 5% of preterm births occur at less than 28 weeks (extreme prematurity), 15% at 28-31 weeks (severe prematurity), 20% at 32-33 weeks (moderate prematurity), and 60-70% at 34-36 weeks (late preterm). Preterm birth may follow preterm labor or premature rupture of membranes. They also may be induced for obstetrical reasons such as infection, intrauterine growth retardation or preeclampsia. However, in many situations, the cause for preterm birth remains elusive and unknown.
Premature infants are at greater risk for short and long term complications. In particular, during the first week of life, many preterm infants, particularly infants born at less than 32 gestational weeks and very low birth weight infants (birth weight of less than 1,500 g), develop hyperglycaemia. The hyperglycaemia is particularly common on day 2 and 3 after birth and is associated with both mortality and morbidity. The pathogenesis of this hyperglycaemia is complex and not clear. However, it seems to be related to defective islet beta-cell processing of proinsulin and to early and persistent reduction in insulin sensitivity of preterm infants (Mitanchez, 2008). Intracellular glucose deprivation, a consequence of low postnatal insulin levels, may also initiate counterregulatory responses and catabolism, leading to hyperglycaemia.
In addition to hyperglycaemia, a large proportion of preterm infants show evidence of postnatal growth impairment irrespective of whether birth weight was appropriate (AGA) or small for gestational age (SGA). The timing and magnitude of catch-up growth is very variable and long term studies suggest that final height may be significantly affected (Finken et al., 2006). For full-term SGA infants, the majority achieved catch-up growth during the first 2 years of life, and most of the increase in height occurred by several months of age, mostly by six months. However, SGA children who remained short at 2 years of age (about 10%) had a higher risk of short stature later in life (Albertsson-Wikland et al., 1998).
Previous studies on circulating growth factors related to in-utero or ex-utero growth restraints showed that IGF-I and IGF-2 mediates the majority of the growth-promoting effects of growth hormone (GH) before birth in humans, whereas IGF-I and growth hormone are the major post-natal factors. Indeed, deletions in the IGF-1 gene result in severe pre- and post-natal growth and developmental defects and in mental retardation (Woods et al., 1996). Furthermore, it was also demonstrated that, at birth, when analyzed according to gestational age, serum insulin-like growth factor-I (IGF-I) level was decreased in intrauterine growth-retarded children as compared with normal neonates. During the first 3 months of life, a positive correlation was also found between IGF-I increment and weight gain (Leger et al., 1996).
IGF-1 is a trophic factor that circulates at high levels in the blood stream. The majority of circulating IGF-1 is produced in the liver. However, many other tissues including bone, adipose tissue, kidney, and muscle also produce IGF-1 and are sensitive to its action, especially during postnatal development. The regulation of IGF-1 production in hepatic tissue is mainly mediated by growth hormones and insulin. In turn, IGF-1 feeds back to suppress growth hormones and insulin release (Pavelic et al., 2007).
A pilot study showed that intravenous administration of insulin throughout the first week of life in very low birth weight infants improves blood glucose control and increases IGF-I levels (Beardsall et al., 2007). This study led to the Neonatal Insulin Therapy in Europe (NIRTURE) Trial involving 194 very-low-birth-weight infants and aiming to determine whether early insulin replacement reduced hyperglycaemia and affected outcomes in such neonates. Results of this trial confirmed that early insulin replacement by intravenous administration improved glucose control and reduced weight loss in the first week of life but also increased risk of hypoglycaemia (Beardsall et al., 2008). This trial was finally stopped because of concerns that the primary outcome of mortality at the expected date of delivery was ineffective and because of concerns of potential harm. Administration of insulin therapy in preterm and/or low birth weight infants thus remains controversial.
Accordingly, there is a strong need for an alternative safe method for treating hyperglycaemia in preterm or low birth weight infants and promoting their catch-up growth.